Of all the reactive transitional metabolites that are potentially toxic per se, or combine with naturally occurring chemical moieties to produce harmful substances, homocysteine is one of the most relevant and important for human health and disease. Its elevation correlates highly with some of the most prevalent human illnesses, including cardiovascular disorders, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects (Refsum. H. et al. (2004) Clin Chem. 50: 3-32).
Homocysteine is formed by demethylation of the essential amino acid, methionine. In the cell, methionine is partitioned between protein synthesis and the formation of S-adenosylmethionine (SAMe). SAMe is the most central methylating agent in the cell, and the only methyl donor in the central nervous system. The product of methylation reactions involving SAMe is S-adenosylhomocysteine (SAH), which is reversibly hydrolyzed to homocysteine. In most tissues, homocysteine may be remethylated to methionine, and hence to SAMe, by the enzyme methionine synthase (MS). This reaction requires vitamin B12 as a cofactor and methyltetrahydrofolate as substrate. In certain tissues, mainly liver and kidney, the enzyme betaine homocysteine methyltransferase (BHMT) provides an alternate pathway for the remethylation of homocysteine to SAMe, using betaine as a substrate. In the transsulfuration pathway, homocysteine may be condensed irreversibly with serine to cystathionine and cysteine in two vitamin B6-dependent reactions. Cysteine is a precursor of glutathione (GSH), the major redox buffer in the cell. For further review of homocysteine metabolism pathways, see Selhub, J. (1999) Annu. Rev. Nutr. 19: 217-246; Finkelstein, J. D. (2000) Seminars in Thrombosis and Hemostasis 26: 219-225; Kruger, W. D. (2000) Vitamins and Hormones 60: 333-352.
In the metabolic pathways, homocysteine sits downstream of the most central methylating agent, S-adenosylmethionine (SAMe), and it sits upstream of some very common bottlenecks or blockages in the metabolic pathways. These blockages could take the form of genetic polymorphisms affecting enzymes in this pathway, or the pathway of its co-enzymes, such as folate metabolism. Alternatively, upstream accumulation of homocysteine might reflect a nutritional deficiency, life style factors or other strains to the homeostatic mechanisms that regulate the metabolic pathways.
Homocysteine itself is a toxic waste product, and not merely an indicator of a road block in the methylation—remethylation cycle. Homocysteine may be converted to the reactive toxin, homocysteine-thiolactone (see Jacubowski, H., and Goldman, E., (1993) FEBS Lett. 317: 237-240).
SAMe, the product of homocysteine re-methylation, regulates gene expression and helps prevent genetic mutations; it maintains mitochondrial function; it participates in phospholipid synthesis and maintains the integrity of cell membranes; and it regulates neurotransmitters such as serotonin, dopamine and epinephrine (adrenaline), and hormones such as estrogen and melatonin.
Administering SAMe to subjects has been found to have a variety of salutary effects. U.S. Pat. No. 5,166,328 and U.S. application Ser. No. 2002/0025926, the disclosures of which are incorporated herein by reference, describe some of these effects in the brain: it inhibits neuron death following ischemia; it improves the utilization of glucose in the brain; it inhibits brain edema; it improves EEG and evoked potential findings by normalizing them; and it improves motor function, such as that impaired by stroke. SAMe has been found, for example in meta-analyses of multiple drug studies, to enhance emotional well-being and is as effective as many common prescription drugs—tricyclics such as Elavil® (amitriptyline HCl) and Norpramin® (desipramine hydrochloride), and Selective Serotonin Reuptake Inhibitors (SSRIs) such as Prozac® (fluoxetine hydrochloride), Zoloft® (sertraline hydrochloride), and Paxil® (paroxetine hydrochloride)—in treating depression, but with significantly fewer side effects than any of these drugs. SAMe has also been used to treat anxiety, chronic pain, arthritis, rheumatoid fibromyalgia, Chronic Fatigue Syndrome, cognitive difficulties associated with Alzheimer's Disease, neurovascular disease and neurological conditions associated with AIDS. In addition to diseases of the central and peripheral nervous system, SAMe has been found to improve diseases of the joints, cardiovascular system, and liver.
Administering compounds that decrease homocysteine to subjects has been found to have a variety of salutary effects. Anti-homocysteine agents have been used to treat cognitive and neurological disorders, including senile dementia and depression (Godfrey, P. S. A. et al. (1992) Br. J. Psychiatry 161: 126-127) and cardiovascular disorders such as atherothrombotic cerebrovascular disease, (Verneulen, E. G. et al., (2000) Neth. J. Med. 56: 138-146).